The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma

Abstract

IntroductionThe ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas.MethodsWe used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging.ResultsAnimals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days.ConclusionsKC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma

“…It has been postulated that a ketogenic diet, i.e., a diet consisting of high fat, low carbohydrates and adequate protein, may be useful in the treatment of brain tumors (25)(26)(27)(28)(29)(30)(31). The present study was conducted to assess the therapeutic efficacy and safety of a KD concomitant with intranasal perillyl alcohol as a novel therapeutic strategy for recurrent GBM.…”

“…For example, among groups of mice with luciferase-labeled GL261 glioma cells implanted into their brains, median survival time was significantly extended in mice on a KD compared with mice on a standard diet; in addition, when such mice received two fractions of radiation (2x4 Gy of whole brain radiation), the bioluminescent signals from the intracranial tumors was diminished below the detectable limit in 82% of the mice, and no signs of tumor recurrence were observed for >200 days (27).…”

The ketogenic diet for the treatment of malignant glioma

“…The UKD greatly enhanced survival in a mouse model of glioma when combined with TMZ when compared with either treatment alone ( 68 ). In addition, a separate study showed that 9 out of 11 animals maintained on the UKD and treated with radiation had complete and sustained remission of their implanted tumors, even after being switched back to a standard rodent diet ( 58 ). Another recent study Tumors not only stimulate rapid angiogenesis, but these blood vessels often develop immaturely and become very leaky ( 52 ).…”

“…Thus, this approach may meet with less resistance from the clinical community. Recent studies have shown that the UKD also causes a reduction in blood glucose, an elevation of blood ketones, and extends life in an immunocompetent mouse model of malignant glioma ( 57,58 ). In the GL261 mouse glioma model, the UKD decreased tumor vasculature, reduced peritumoral edema, and altered the expression of genes involved in angiogenesis (Woolf et al ., unpublished observations), paralleling the CR results mentioned above.…”

Nutritional Problems in Head and Neck Cancer Patients

“…The studies by Abdelwahab et al [25] seem very important, as these researchers attempted to evaluate the influence of a ketogenic diet with limited amounts of carbohydrates on the development of neoplasms in mice. Decreased production of reactive oxygen species in cells was observed, as was a decreased expression of genes that play a role in the transduction of growth signals that play a key role in neoplasm progression [25]. There is little information in the literature concerning the use of a low-carbohydrate diet or low glycemic index diet in human subjects.…”